Inhibitor for narcotic analgesic dependence/resistance acquisition

ABSTRACT

A medicament which comprises as an active ingredient a compound represented by the following formula: R 2  -CH 2  CONH-R 1  wherein R 1  represents a pyridyl group, a substituted pyridyl group, phenyl group, or a substituted phenyl group; and R 2  represents 2-oxo-1-pyrrolidinyl group which may optionally be substituted, and inhibits the development of dependency induced by a narcotic analgesic and/or inhibit the development of tolerance to analgesic action induced by a narcotic analgesic agent.

This application is a 371 PCT/SP96/02207, filed Aug. 6, 1996.

TECHNICAL FIELD

The present invention relates to a medicament for inhibitingdevelopments of dependency and tolerance to analgesic action which areinduced by the administration of a narcotic analgesic agent.

BACKGROUND ART

Narcotic analgesic agents, e.g., morphine, have excellent analgesicaction against visceral pains or other, and are clinically used foralleviation of pain for terminal cancer patients. However, the narcoticanalgesic agents are typical drugs that affect on mental functions anddevelop psychic and physical dependency. In addition, tolerance toanalgesic action, as being their primary efficacy, is rapidly developedby repeated administrations. Accordingly, carefully controlled frequencyof administration and dose are required to achieve a desired analgesicaction, while maintaining minimized development of dependency.

Therefore, when a narcotic analgesic agent such as morphine is used, itis necessary to inhibit the development of tolerance to analgesicactivity without reducing analgesic activity to meet the purpose of theuse. It is also important to inhibit the development of dependency.

An object of the present invention is to provide a medicament havinginhibitory activity against the development of dependency induced by theadministration of the narcotic analgesic agent such as morphine. Anotherobject of the present invention is to provide a medicament havinginhibitory activity against the development of tolerance to analgesicaction induced by the administration of the narcotic analgesic agentsuch as morphine. A further object of the present invention is toprovide a medicament having both of the aforementioned pharmacologicalactivities.

DISCLOSURE OF THE INVENTION

The inventors of the present invention conducted various studies toachieve the foregoing objects, and as a result, they found that2-(1-pyrrolidinyl)acetamide derivatives, which are useful as medicamentsfor improving cerebral functions, have the aforementionedpharmacological activities. They also found that the derivatives areuseful as active ingredients of medicaments which inhibit thedevelopments of dependency and/or the developments of tolerance toanalgesic actions induced by narcotic analgesic drugs. The presentinvention was achieved on the basis of these findings.

The present invention thus provides a medicament which comprises as anactive ingredient a compound represented by the following formula: R²-CH₂ CONH-R¹ wherein R¹ represents a pyridyl group, a substitutedpyridyl group, phenyl group, or a substituted phenyl group; and R²represents 2-oxo-1-pyrrolidinyl group which may optionally besubstituted, and inhibits the development of dependency induced by anarcotic analgesic agent and/or inhibits the development of tolerance toanalgesic action induced by a narcotic analgesic agent.

According to preferred embodiments of the present invention, thefollowing inventions are provided: the aforementioned medicament whichinhibits the development of dependency induced by a narcotic analgesicagent, and also inhibits the development of tolerance to analgesicaction induced by a narcotic analgesic agent; the aforementionedmedicament which inhibits the development of dependency induced by anarcotic analgesic agent; the aforementioned medicament which inhibitsthe development of tolerance to analgesic action induced by a narcoticanalgesic agent; the aforementioned medicament used in combination witha narcotic analgesic agent; the aforementioned medicament having aprophylactic effect to reduce or prevent the development of dependencyinduced by a narcotic analgesic agent and/or the development oftolerance to analgesic action induced by a narcotic analgesic agent; theaforementioned medicament having a therapeutic effect to reduce oreliminate dependency already developed by a narcotic analgesic agentand/or tolerance to analgesic action already developed by a narcoticanalgesic agent; the aforementioned medicament wherein said activeingredient is N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide;the aforementioned medicament wherein said narcotic analgesic agent ismorphine hydrochloride or morphine nitrate; and the aforementionedmedicament which is in the form of a pharmaceutical compositioncomprising said active ingredient together with one or morepharmaceutically acceptable additives.

According to another aspect of the present invention, there is alsoprovided an inhibitory agent against the development of dependencyand/or against the development of tolerance to analgesic action inducedby a narcotic analgesic agent, which comprises as an active ingredient acompound represented by the following formula: R² -CH₂ CONH-R¹ whereinR¹ represents a pyridyl group, a substituted pyridyl group, phenylgroup, or a substituted phenyl group; and R² represents2-oxo-1-pyrrolidinyl group which may optionally be substituted.According to preferred embodiments of this invention, there are providedthe inhibitory agent against the development of dependency induced by anarcotic analgesic agent; and the inhibitory agent against thedevelopment of tolerance to analgesic action induced by a narcoticanalgesic agent.

According to further aspect of the present invention, there is provideda use of a compound represented by the following formula: R² -CH₂CONH-R¹ wherein R¹ represents a pyridyl group, a substituted pyridylgroup, phenyl group, or a substituted phenyl group; and R² represents2-oxo-1-pyrrolidinyl group which may optionally be substituted, for themanufacture of a medicament which comprises said compound as an activeingredient and inhibits the development of dependency induced by anarcotic analgesic agent and/or inhibits the development of tolerance toanalgesic action induced by a narcotic analgesic agent, preferably forthe manufacture of a medicament in the form of a pharmaceuticalcomposition comprising said active ingredient together with one or morepharmaceutically acceptable additives.

In addition to the aforementioned inventions, there is also provided amethod for inhibiting the development of dependency induced by anarcotic analgesic agent and/or inhibiting the development of toleranceto analgesic action induced by a narcotic analgesic agent, whichcomprises the step of administering to a patient a therapeuticallyand/or preventively effective amount of a compound represented by thefollowing formula: R² -CH₂ CONH-R¹ wherein R¹ represents a pyridylgroup, a substituted pyridyl group, phenyl group, or a substitutedphenyl group; and R² represents 2-oxo-1-pyrrolidinyl group which mayoptionally be substituted.

BEST MODE FOR CARRYING OUT THE INVENTION

The active ingredients of the medicament of the present invention, i.e.,the aforementioned 2-(1-pyrrolidinyl)acetamide derivatives, aredisclosed in the Japanese Patent Unexamined Publication (KOKAI) No.(Sho) 56-2960/1981 (the U.S. Pat. No. 4,341,790) as compounds useful forimproving cerebral functions. R¹ represents a pyridyl group, asubstituted pyridyl group, phenyl group, or a substituted phenyl group.Examples of one or more substituents on the ring that constitutes thesubstituted pyridyl group or the substituted phenyl group include, forexample, a halogen atom, trifluoromethyl group, nitro group, acetylgroup, an alkyl group, an alkoxy group, an alkylmercapto group, aminogroup, sulfonyl group, and aminoethoxycarbonyl group.

R² represents 2-oxo-1-pyrrolidinyl group which may optionally besubstituted. As a substituent, for example, hydroxyl group may be used.The aforementioned compounds can be readily prepared according to themethods described in the Japanese Patent Unexamined Publication (KOKAI)Nos. (Sho) 56-2960/1981 and (Hei) 6-65197/1994 (the U.S. Pat. Nos.4,341,790 and 5,461,157, respectively). Among the compounds describedabove, an example of the most preferred compound includesN-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide.

The medicament of the present invention has inhibitory activity againstthe development of dependency induced by a narcotic analgesic agent,and/or inhibitory activity against the development of tolerance toanalgesic action induced by a narcotic analgesic agent. The medicamentof the present invention is characterized to exhibit the above-describedactivities without reducing the analgesic action of a narcotic analgesicagent.

Generally, by using the medicament of the present invention incombination with a narcotic analgesic agent, the medicament can reduceor prevent the development of dependency induced by the narcoticanalgesic agent, and also can reduce or prevent the development oftolerance to analgesic action induced by the narcotic analgesic agent.Accordingly, the medicament of the present invention may be used for aprophylactic purpose to reduce or prevent the aforementioned developmentof dependency and/or development of tolerance. In addition, themedicament of the present invention has reducing and eliminatingactivity on dependency already developed by the administration of anarcotic analgesic agent or tolerance to analgesic action of thenarcotic analgesic agent. Therefore, the medicament of the presentinvention can be used for a therapeutic purpose to reduce or eliminatethe aforementioned already developed dependency and/or tolerance, whilegenerally maintaining a combined administration with a narcoticanalgesic agent.

The narcotic analgesic agents are not particularly limited so far as theagents are recognized to develop dependency by a single administrationor repeated administrations for a short or prolonged period of time,and/or substantially develop tolerance to analgesic action thereof byrepeated administrations for a short or prolonged period of time.Examples of the narcotic analgesic agents include, for example,morphines and their semi-synthesized derivatives derived from opium andnon-natural compounds having morphine-like activity such as petidine;and salts of these compounds.

More specifically, examples of the narcotic analgesic agents include,for example, alkaloids obtained from opium and their semi-synthesizedderivatives such as, for example, phenanthrenes such as morphine,oxymolphone, hydromolphone, codeine, hydrocodeine, heroin, thebaine, andbuprenorphine; phenylpiperidines such as meperidine and fentanyl;phenylheptylamines such as methadone and propoxyphene; morphinans suchas levorphanol, methorphan, and levorphane; and benzomorphans such asphenazocine and pentazocine.

Examples also include analgesic peptides as endogenous morphine-likesubstances such as, for example, enkephalins such as methionineenkephalin and leucine enkephalin; endorphins such as α-endorphin,β-endorphin, and γ-endorphin; and dynorphins such as dynorphin A anddynorphin B, and precursors thereof whose examples includeproenkephalins such as proenkephalins, propiomelanocortins, andprodynorphins.

Opiate receptors on which narcotic analgesic agents can act as agonistsor antagonists are generally classified into three subclasses, i.e., μ,κ, and δ. Among the narcotic analgesic agents, the medicament of thepresent invention may preferably be applied to those can act as agonists(or partial agonists) of μ, κ and/or δ receptors. For example, typicalnarcotic analgesic agents can be classified into the following groupsfrom a viewpoint of their actions on the receptors: morphine, dynorphinB, β-endorphin or other, for example, which acts as an agonist on μreceptor involved in functions leading to analgesic action, miosis,respiratory suppression, euphoria, and dependency at spinal leve;pentazocine or morphine, for example, which acts as an agonist of κreceptor involved in analgesic action, sedation, and miosis at spinallevel; and dynorphin A or β-endorphin, for example, which acts as anagonist of δ receptor involved in affective expression.

Although not intended to be bound by any specific theory, narcoticanalgesic agents such as morphine are known to decrease the inflow ofcalcium ions into neurons, and therefore, it can be elucidated that themedicament of the present invention activates the calcium ion channel,and thereby inhibit the development of dependency and the development oftolerance to analgesic action induced by a narcotic analgesic agent.

Route of administration of the medicament of the present invention isnot particularly limited, and the medicament can be administered orallyand parenterally to humans. The compounds of the aforementioned formula,per se, may be used as the medicament of the present invention. However,it is generally preferable that the medicament is provided as apharmaceutical composition in a form of formulation well known to one ofordinary skilled in the art, by optionally adding one or morepharmacologically and pharmaceutically acceptable additives to theaforementioned compound as an active ingredient. The medicament of thepresent invention may generally be administered separately from anarcotic analgesic agent by simultaneously using a narcotic analgesicagent which, per se, is provided in a form of pharmaceutical formulationsuch as a solution or a tablet.

Methods for the combined administration are not particularly limited.For example, a method comprising the step of continued administrationsof the medicament of the present invention in accord with the entireadministration period of a narcotic analgesic agent; a method comprisingthe step of the administration of the medicament of the presentinvention in need during the administration period of a narcoticanalgesic agent; a method comprising the steps of the administration ofthe medicament of the present invention started prior to theadministration of a narcotic analgesic agent, followed by continuedcombined administrations of a narcotic analgesic agent and themedicament of the present invention; and a method comprising the stepsof continued combined administration of a narcotic analgesic agent andthe medicament of the present invention, followed by continued and soleadministration of the medicament of the present invention after thetermination of the administration of the narcotic analgesic agent. Ifdesired, a pharmaceutical composition comprising a narcotic analgesicagent and the medicament of the present invention (so called "aformulation comprising multiple active ingredients") may be prepared andadministered.

Examples of the pharmaceutical compositions suitable for oraladministration include, for example, tablets, capsules, powders,subtilized granules, granules, solutions, and syrups. Examples of thepharmaceutical compositions suitable for parenteral administrationinclude, for example, injections for subcutaneous, intravenous, andintramuscular injections, drip infusions, suppositories, inhalants,transdermal preparations, transmucosal preparations, and patches.Examples of the pharmacologically and pharmaceutically acceptableadditives include, for example, excipients, disintegrators ordisintegrating aids, binders, lubricants, coating agents, coloringagents, diluents, base materials, solubilizers or solubilizing aids,isotonicities, pH modifiers, stabilizers, propellants, and adhesives.

For example, as pharmacologically or pharmaceutically acceptableadditives for the manufacture of pharmaceutical compositions suitablefor oral, transdermal, or transmucosal administration, pharmaceuticaladditives such as, for example, excipients such as glucose, lactose,D-mannitol, starch, and crystalline cellulose; disintegrators ordisintegrating aids such as carboxymethylcellulose, starch, andcarboxymethylcellulose calcium; binders such as hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, and gelatine;lubricants such as magnesium stearate and talc; coating agents such ashydroxypropylmethylcellulose, saccharose, polyethylene glycol, andtitanium oxide; and base materials such as vaseline, liquid paraffin,polyethylene glycol, gelatin, china clay, glycerin, purified water, andhard fat may be used. Pharmaceutical additives such as propellants suchas flons, diethyl ether, and compressed gases; adhesives such as sodiumpolyacrylate, polyvinyl alcohol, methylcellulose, polyisobutylene, andpolybutene; and base cloths such as cotton cloth and plastic sheets maybe used for the manufacture of the pharmaceutical compositions.

Pharmaceutical compositions suitable for the use as injections and dripinfusions may be added with, for example, solubilizers or solubilizingaids such as distilled water for injection, physiological saline, andpropylene glycol which can constitute aqueous injections or injectionsdissolved before use; isotonicities such as glucose, sodium chloride,D-mannitol, and glycerin; pH modifiers such as inorganic acids, organicacids, inorganic bases, and organic bases.

Doses and dosing period of the medicament of the present invention arenot particularly limited and they may suitably be chosen depending on,for example, administration route, a degree of the development ofdependency and/or the development of tolerance, purpose ofadministration such as prophylactic or therapeutic administration, andthe age or body weight of a patient. As to examples of the dose, where anarcotic analgesic agent such as morphine hydrochloride, morphinenitrate, or a sustained-release formulation thereof is administered in adose of from about 10 to 30 mg per day from once to three times a day,the medicament of the present invention may be applied to a combinedadministration in a dose of, for example, from 200 to 2,000 mg,preferably from 300 to 900 mg per day as a weight of an activeingredient. The above-described daily dose may be administered severaltimes a day as divided portions. Where the medicament of the presentinvention is administered repeatedly at a high dose, it is preferablethat the dose should be appropriately chosen under the monitor ofinhibitory activity against the development of tolerance to analgesicaction. As to the dosing period, it is desirable that the medicament ofthe present invention is administered as long as possible for the entireadministration period of a narcotic analgesic agent.

EXAMPLES

The present invention will be explained more specifically by referringto examples. However, the scope of the present invention is not limitedto the examples set out below. In the examples,N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl-acetamide (generic name"nefiracetam," referred to as "the medicament of the present invention"in the examples set out below) was used as the medicament according tothe present invention. Each of the medicament of the present inventionand morphine was dissolved in physiological saline. Control group wasadministered only with physiological saline.

Example 1: Effect of the medicament of the present invention on theanalgesic action induced by an acute administration of morphine

Effects on the analgesic action of morphine and the development oftolerance were studied using ddY male mice according to tail-flick test,one of experimental tests for evaluating analgesic action in whichthermal stimulations are applied. The medicament if the presentinvention (5 or 10 mg/kg) was orally administered to the mice, and themorphine (3 or 6 mg/kg) was subcutaneously administered in their backafter 15 minutes. Tail-flick tests were carried out one hour after themorphine administration. Three measurements were performed for each ofthe mice and an average value was recorded as a result for the mouse.Cut off time of the measurement was adjusted to 10 seconds, and where notail-flick reaction was observed for 10 seconds or more, tail-flicklatency was recorded as 10 seconds.

As shown Table 1, morphine dose-dependently prolonged tail-flick latencyand exhibited analgesic action. Pre-treatment with the medicament of thepresent invention 15 minutes prior to the morphine administration didnot affect the analgesic action of morphine, and no reduction of theanalgesic action of morphine by the medicament of the present inventionwas observed. In addition, no analgesic action of the medicament of thepresent invention, per se, was observed. In Table 1, nefiracetam 5mg/kg, and 10 mg/kg represent the administrations of 5 and 10 mg/kg ofthe medicament of the present invention, respectively (the same intables below), and the symbols "a " and "aa" indicate p<0.05 and p<0.01v.s. physiological saline (pre-administration+physiological saline(post-administration), respectively.

                  TABLE 1                                                         ______________________________________                                        Nefiracetam                                                                             Morphine           Tail-flick latency                               (mg/kg)   (mg/kg)      N     (second)                                         ______________________________________                                        0         0            9     3.97 ± 0.33   .sup.                           5         0            9     4.41 ± 0.34   .sup.                           10        0            9     4.21 ± 0.32   .sup.                           0         3            9     7.09 ± 0.84 a .sup.                           5         3            9     8.01 ± 0.85 aa                                10        3            9     8.09 ± 0.66 aa                                0         6            9     9.66 ± 0.23 aa                                5         6            9     8.87 ± 0.63 aa                                10        6            9     8.67 ± 0.78 aa                                ______________________________________                                    

Example 2: Effects of the medicament of the present invention on thedevelopment of tolerance to the analgesic action induced by repeatedadministration of morphine.

After approximately one month of pause of administration of drug fromthe acute administration test, repeated administration test was started.The medicament of the present invention (5 or 10 mg/kg) was orallyadministered to the mice, and then the mice were subcutaneouslyadministered with morphine (6 or 20 mg/kg) in their backs after 15minutes. The drug administrations were carried out twice a day in themorning and evening for 5 days in total. On the 6th day, morphine wasadministered subcutaneously (6 mg/kg), and one hour after theadministration, tail-flick test were performed according to the methoddescribed above, except that the cut off of the tail-flick latency wasprovided for 15 seconds.

As shown in Table 2, shortened tail-flick latencies, i.e., developmentsof tolerance to analgesic action of morphine, were observed by therepeated administrations of morphine. On the other hand, the developmentof tolerance induced by the repeated administration of morphine (6mg/kg) was inhibited by the combined administration of the medicament ofthe present invention (5 mg/kg). The combined administration of themedicament of the present invention (10 mg/kg) reduced the degree of thedevelopment of the tolerance.

In addition, a tendency of reduced tolerance was observed as to thedevelopment of tolerance induced by the repeated administration ofmorphine at a high dose (20 mg/kg). When morphine was administered tomice which had been administered repeatedly with the medicament of thepresent invention, no effect on the analgesic action of morphine wasobserved. In Table 2, the symbols represent:

"a" and "aa": p<0.05 and p<0.01 v.s. control (physiologicalsaline+physiological saline) treatment, respectively;

"b" and "bb": p<0.05 and p<0.01 v.s. subacute (physiologicalsaline+physiological saline) treatment, and

"cc": p<0.01 v.s. subacute (physiological saline+morphine 6 mg/kg)treatment.

                  TABLE 2                                                         ______________________________________                                                Morphine     Morphine                                                 Nefiracetam                                                                           1.sup.st to 5.sup.th day × 2                                                         6.sup.th day  Tail-flick                                 (mg/kg) (mg/kg)      (mg/kg)  N    latency (sec.)                             ______________________________________                                        (Control)                                                                     0       0            0        7    3.70 ± 0.13                             (Combined administration group)                                               0       0            6        16     11.21 ± 0.77 aa                       5       0            6        9      10.15 ± 1.31 aa                       10      0            6        9      10.30 ± 1.33 aa                       0       6            6        16     4.98 ± 0.27 bb                        5       6            6        16      .sup. 9.15 ± 1.12 cc                 10      6            6        16     6.91 ± 0.66 bb                        0       20           6        16     4.58 ± 0.70 bb                        5       20           6        16     6.96 ± 0.73 bb                        10      20           6        15     7.20 ± 0.92 b                         20      20           6        14     7.10 ± 0.99 b                         ______________________________________                                    

Example 3: Effect of the medicament of the present invention on thedevelopment of physical dependency induced by repeated administration ofmorphine

The medicament of the present invention was orally administered (5 or 10mg/kg) to mice, and then morphine was subcutaneously administered intheir backs (6 or 20 mg/hg) after 15 minutes. The drug administrationwas carried out twice a day in the morning and evening for 5 days intotal. The same treatment was once performed on the 6th day, and thennaloxone was administered (5 mg/kg, i.p.) after two hours.

Withdrawal symptoms induced by the naloxone administration, includingjumping, wet dog shake, and diarrhea, were observed for 30 minutesimmediately after the naxalone administration. Losses of body weightswere also measured. The results are shown in Table 3. In Table 3, thesymbols represent: "a" and "aa": p<0.05 and p<0.01 v.s. subacute(physiological saline+physiological saline) treatment, respectively; "b"and "bb": p<0.05 and p<0.01 v.s. subacute (physiological saline+morphine6 mg/kg) treatment, respectively; and "c": p<0.05 v.s. subacute(physiological saline+morphine 20 mg/kg) treatment.

                  TABLE 3                                                         ______________________________________                                        Nefiracetam Morphine           Withdrawal                                     (mg/kg)           (mg/kg)                                                                             N          symptom                                    ______________________________________                                        (Combined administration group) (Jumping)                                     0           0        17         0.94 ± 0.67                                5                0           19                                                                                   0.79 ± 0.79                            10              0            19                                                                                   0.00 ± 0.00                            0                6           18                                                                                 11.39 ± 3.23                             5                6           18                                                                                   1.72 ± 1.37 b                          10              6            18                                                                                   2.61 ± 1.27 b                          0               20           18                                                                                 13.94 ± 3.82 a                           5               20           18                                                                                   8.50 ± 3.79                            10             20            18                                                                                   4.00 ± 1.61                            (Combined administration group) (Wet dog shake)                               0           0        17         0.18 ± 0.13                                5               0             19                                                                                  0.53 ± 0.25                            10             0              19                                                                                  0.32 ± 0.13                            0               6             18                                                                                  2.06 ± 0.80                            5               6             18                                                                                  1.89 ± 0.83                            10             6              18                                                                                  2.17 ± 0.56                            0               0             18                                                                                  1.39 ± 0.52                            5               20           18                                                                                   0.94 ± 0.31                            10             20            18                                                                                   1.22 ± 0.52                            (Combined administration group)  (Loss of body weight)                        0           0        17        -0.21 ± 0.10                                5               0             19                                                                                -0.21 ± 0.08                             10             0              19                                                                                -0.08 ± 0.04                             0               6             18                                                                                -1.11 ± 0.21 aa                          5               6             18                                                                                -0.42 ± 0.11 bb                          10             6              18                                                                                -0.44 ± 0.11 b                           0               20           18                                                                                 -0.97 ± 0.15 aa                          5               20           18                                                                                 -0.83 ± 0.20                             10             20            18                                                                                 -0.72 ± 0.13                             (Combined administration group)  (Diarrhea)                                   0           0        17         0.24 ± 0.14                                5               0             19                                                                                  0.05 ± 0.05                            10             0              19                                                                                  0.00 ± 0.00                            0               6             18                                                                                  1.39 ± 0.18 aa                         5               6             18                                                                                  0.50 ± 0.17 bb                         10             6              18                                                                                  0.44 ± 0.17 b                          0               20           18                                                                                   1.44 ± 0.15 aa                         5               20           18                                                                                   0.78 ± 0.21 c                          10             20            18                                                                                   0.83 ± 0.20                            ______________________________________                                    

In the groups repeatedly administered with morphine, jumping symptom wasincreased dose-dependently with morphine administration. In the groupadministered with 6 mg/kg morphine, the above symptom was inhibited bythe pre-treatment with the medicament of the present invention (5 and 10mg/kg). In the group administered with 20 mg/kg morphine, a tendency wasobserved that the development of dependency was inhibiteddose-dependently with the administration of the medicament of thepresent invention. In addition, as to wet dog shake, a tendency of theincrease of the symptom was observed in the group administered withmorphine, although no statistical difference was observed as compared tothe control group due to a small numerical numbers of the observedsymptoms.

Diarrhea was enhanced in the groups repeatedly administered withmorphine. However, significant inhibition of the enhancement of diarrheawas achieved in the group administered repeatedly with 6 mg/kg morphinewhich was pre-treated with the medicament of the present invention (5and 10 mg/kg). Furthermore, in the group administered with 20 mg/kgmorphine, the enhancement of diarrhea was significantly inhibited by thepre-treatment with the medicament of the present invention (5 mg/kg). Asto the loss body weight, significant body weight losses were observed inthe groups administered repeatedly with morphine. However, the loss ofbody weight was inhibited in the group administered with 6 mg/kgmorphine which was pre-treated with the medicament of the presentinvention (5 and 10 mg/kg). A tendency was observed in the groupadministered with 20 mg/kg morphine that the developments of dependencywas inhibited dose-dependently with the administration of the medicamentof the present invention.

Industrial Applicability

The medicament of the present invention is useful because the medicamenthas inhibitory activities against the development of dependency and thedevelopment of tolerance to analgesic action induced by theadministration of a narcotic analgesic agent.

What is claimed is:
 1. A method of at least one of inhibitingdevelopment of dependency induced by a narcotic analgesic agent andinhibiting development of tolerance to analgesic action induced by anarcotic analgesic agent, comprising:administering a narcotic analgesicagent; administering at least one of a therapeutically effective amountand a preventively effective amount of a medicament to at least one ofinhibit development of dependency induced by the narcotic analgesicagent and inhibit development of tolerance to analgesic action inducedby the narcotic analgesic agent; and wherein the medicament comprises anactive ingredient represented by the following formula: R² -CH₂ CONH-R¹wherein R¹ represents a pyridyl group, a substituted pyridyl group,phenyl group, or a substituted phenyl group; and R² represents2-oxo-1-pyrrolidinyl group which may optionally be substituted.
 2. Themethod of claim 1, wherein the at least one of inhibiting development ofdependency induced by the narcotic analgesic agent and inhibitingdevelopment of tolerance to analgesic action induced by the narcoticanalgesic agent comprises inhibiting the development of dependencyinduced by the narcotic analgesic agent and inhibiting the developmentof tolerance to analgesic action induced by the narcotic analgesicagent.
 3. The method of claim 1, wherein the at least one of inhibitingdevelopment of dependency induced by the narcotic analgesic agent andinhibiting development of tolerance to analgesic action induced by thenarcotic analgesic agent comprises inhibiting the development ofdependency induced by the narcotic analgesic agent.
 4. The method ofclaim 1, wherein the at least one of inhibiting development ofdependency induced by the narcotic analgesic agent and inhibitingdevelopment of tolerance to analgesic action induced by the narcoticanalgesic agent comprises inhibiting the development of tolerance toanalgesic action induced by the narcotic analgesic agent.
 5. The methodof claim 1, wherein the medicament has a prophylactic effect to at leastone of:reduce or prevent the development of dependency induced by thenarcotic analgesic agent, and reduce or prevent the development oftolerance to analgesic action induced by the narcotic analgesic agent.6. The method of claim 1, wherein the medicament has a therapeuticeffect to at least one of:reduce or eliminate dependency alreadydeveloped by the narcotic analgesic agent, and reduce or eliminatetolerance to analgesic action already developed by the narcoticanalgesic agent.
 7. The method of claim 1, wherein the active ingredientcomprises N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide. 8.The method of claim 1, wherein the narcotic analgesic agent is one ofmorphine hydrochloride and morphine nitrate.
 9. The method of claim 1,wherein the medicament comprises a pharmaceutical composition comprisingthe active ingredient together with at least one pharmaceuticaladditive.
 10. The method of claim 1, wherein the administering of themedicament is carried out during administration of the narcoticanalgesic agent.
 11. The method of claim 1, wherein the administering ofthe medicament is carried out before administration of the narcoticanalgesic agent.
 12. The method of claim 1, wherein the administering ofthe medicament is carried out after administration of the narcoticanalgesic agent.
 13. The method of claim 1, wherein the narcoticanalgesic agent is administered at a dosage of about 10 to 30 mg per dayfrom once to three times a day.
 14. The method of claim 1, wherein themedicament is administered at a dosage of from 200 to 2000 mg per day,based on weight of the active ingredient.
 15. The method of claim 1,wherein the medicament is administered at a dosage of from 300 to 900 mgper day, based on weight of the active ingredient.
 16. The method ofclaim 1, wherein the narcotic analgesic agent is administered at adosage of about 10 to 30 mg per day from once to three times a day, andwherein the medicament is administered at a dosage of from 200 to 2000mg per day, based on weight of the active ingredient.
 17. The method ofclaim 1, wherein the medicament is administered at a dosage of from 200to 2000 mg per day, based on weight of the active ingredient, andwherein the medicament is administered at a dosage of from 300 to 900 mgper day, based on weight of the active ingredient.
 18. The method ofclaim 1, wherein R¹ represents substituted pyridyl group, and whereinthe substituted pyridyl group comprises at least one substituentselected from the group consisting of halogen atom, trifluoromethylgroup, nitro group, acetyl group, alkyl group, alkoxy group,alkylmercapto group, amino group, sulfonyl group, andaminoethoxycarbonyl group.
 19. The method of claim 1, wherein R¹represents substituted phenyl group, and wherein the substituted phenylgroup comprises at least one substituent selected from the groupconsisting of halogen atom, trifluoromethyl group, nitro group, acetylgroup, alkyl group, alkoxy group, alkylmercapto group, amino group,sulfonyl group, and aminoethoxycarbonyl group.
 20. The method of claim1, wherein the narcotic analgesic agent comprises an alkaloid.
 21. Themethod of claim 1, wherein the narcotic analgesic agent comprises ananalgesic peptide.
 22. A method of at least one of inhibitingdevelopment of dependency induced by a narcotic analgesic agent andinhibiting development of tolerance to analgesic action induced by anarcotic analgesic agent in a patient who has been administered anarcotic analgesic agent, comprising:administering at least one of atherapeutically effective amount and a preventively effective amount ofa medicament to at least one of inhibit development of dependencyinduced by the narcotic analgesic agent and inhibit development oftolerance to analgesic action induced by the narcotic analgesic agent;and wherein the medicament comprises an active ingredient represented bythe following formula: R² -CH₂ CONH-R¹ wherein R¹ represents a pyridylgroup, a substituted pyridyl group, phenyl group, or a substitutedphenyl group; and R² represents 2-oxo-1-pyrrolidinyl group which mayoptionally be substituted.
 23. The method of claim 22, wherein theactive ingredient comprisesN-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide.
 24. The methodof claim 22, wherein the narcotic analgesic agent is one of morphinehydrochloride and morphine nitrate.
 25. The method of claim 22, whereinthe medicament is administered at a dosage of from 200 to 2000 mg perday, based on weight of the active ingredient.
 26. The method of claim22, wherein the medicament is administered at a dosage of from 300 to900 mg per day, based on weight of the active ingredient.